The effects of polymeric
IgA1 (pIgA1) and monomeric
IgA1 (mIgA1) from patients with
IgA nephropathy (IgAN) on the renin-angiotensin system (RAS) and
TGF-beta synthesis were examined in cultured human mesangial cells (HMC). Both pIgA1 and mIgA1 induced
renin gene expression in HMC, in a dose-dependent manner. Similar findings were observed for
TGF-beta gene and
protein expression. The values measured in HMC incubated with pIgA1 were significantly higher than those in HMC incubated with equivalent amounts of mIgA1. When similar experiments were performed with the addition of either
captopril or
losartan, there was a significant increase in the
renin gene expression by HMC, whereas the synthesis of
TGF-beta was markedly reduced. The
TGF-beta signal transduction pathways in HMC were studied by measuring the
receptor-regulated Smad proteins (Smad 2 and 3) and common-partner
Smad proteins (Smad 4). pIgA1 from patients with IgAN upregulated Smad activity in HMC, and the activity observed in HMC that had been preincubated with pIgA1 was readily suppressed with optimal concentrations of
captopril or
losartan. The effects of pIgA1 on the RAS were further examined in HMC incubated with
IgA isolated from 30 patients with IgAN, 30 healthy subjects, and disease control subjects with other diseases. pIgA1 induction of
angiotensin II or
TGF-beta synthesis in HMC was significantly greater with preparations from patients with IgAN, compared with healthy or disease control subjects. The findings support a pathogenetic role of pIgA1 in IgAN through upregulation of the RAS and
TGF-beta, leading to
chronic renal failure with renal
fibrosis.